Thalidomide: From Tragic Birth Defects to Treating Cancer

Thalidomide is a sedative drug developed by the German pharmaceutical company Chemie Grünenthal in the late 1950s to treat nausea. Despite a lack of rigorous scientific research, Grünenthal assured that thalidomide was safe for pregnant women to consume, and it was consequently prescribed to treat morning sickness and pregnancy-associated insomnia (The New York Times, 2013). In 1961, evidence came to light linking prenatal thalidomide toxicity to a range of congenital malformations, known as teratogenesis, in German babies (Bastow et al., 2017). It is estimated that 15,000 children worldwide were born with malformations attributable to thalidomide. Many newborns died a few days after birth while surviving babies most commonly suffered from Phocomelia (shortening of the arms and legs) (Thalidomide victims association of Canada, 2014). Following what was one of the most horrifying episodes in medical history, thalidomide was banned in 1962. However, new therapeutic effects of the drug have since been discovered, such as alleviating symptoms of leprosy and treating certain cancers (The New York Times, 2013). Since its scientific rehabilitation in the 1990s, thalidomide and its analogues have become the primary treatments for multiple myeloma. However, the reintroduction of thalidomide has been accompanied by several ethical issues. In Brazil, where the drug is used extensively to treat leprosy, hundreds of thalidomide children have been born since 2005 (MacDougall, 1998). In this essay, I will outline the molecular mechanisms linking prenatal thalidomide exposure to teratogenesis, and describe the pathways through which thalidomide can have such diverse physiological effects. I will also argue that, provided they remain stringently regulated, thalidomide and its analogues have the potential to improve the lives of millions of people worldwide, and thus they should not be banned.  

Thalidomide and its analogues lenalidomide and pomalidomide are small molecules synthetically derived from glutamic acid which are collectively known as immune-modulating drugs (IMiDs). Aside from their extensive use to treat leprosy and multiple myeloma, IMiDs have also been prescribed against a wide range of other diseases, such as Multiple Sclerosis, Tuberculosis, Crohn's Disease and AIDS (Stewart, 2014). Meanwhile, the range of birth defects attributed to thalidomide is as widespread as its medical benefits; thalidomide embryopathy can affect the limbs, face, eyes, ears, genitalia and internal organs, including the heart, kidney, and gastrointestinal tract, with an infant mortality of around 40%, likely attributed to internal organ damage (Vargesson, 2015). For many years, the biochemical nature of these diverse effects was largely unknown. However, recent studies have greatly enhanced our understanding of the molecular mechanisms of thalidomide and other IMiDs. 

The anti-angiogenic properties of IMiDs were first discovered in 1992. Angiogenesis is the physiological process through which new blood vessels sprout from pre-existing vasculature, which is essential for tumour growth and metastasis (D’Amato et al., 1994). Using an aortic ring assay as an angiogenesis model, studies showed that thalidomide could starve blood flow to cells, giving it potential anti-cancer properties (Price et al., 2002). Thalidomide inhibits angiogenesis by trans-activating the enzyme acid sphingomyelinase (SMase), which in turn catalyses the breakdown of sphingomyelin into ceramide and phosphorylcholine. Ceramide inhibits the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) signalling pathways, both of which play central roles in angiogenesis (Yabu et al., 2005). Thalidomide also suppresses angiogenesis by interacting with cereblon (CRBN), thereby inhibiting the E3 ubiquitin-ligase activity of the CRBN/DDB-1/Cul4 complex. The direct ubiquitination targets of this complex have not been fully elucidated, however, studies indicate that the antagonism of cereblon by thalidomide reduces the levels of FGF8 and FGF10 (Kawamura et al., 2014). By limiting VEGF and FGF activities, thalidomide also induces loss of newly formed blood vessels during critical stages in limb development, causing cell death and teratogenicity. 

Surprisingly, the interaction of lenalidomide with CRBN stimulates the CRBN/DDB-1/Cul4 E3 ubiquitin ligase to target the transcriptional regulator Ikaros for degradation. The degradation of Ikaros enhances IL-2 expression, which promotes differentiation of T cells and stimulates natural killer (NK) cell-mediated killing of multiple myeloma cells (Ito et al., 2010) (Lu et al., 2014). The inhibition of CRBN by thalidomide has been shown to be necessary but insufficient to induce teratogenicity in Zebrafish. In humans, CRBN mutations cause autosomal recessive mental retardation, but are not associated with limb defects, indicating that the combined effects of multiple pathways contribute to teratogenesis (Davies et al., 2001). 

Indeed, thalidomide, lenalidomide and pomalidomide have been found to also contribute to teratogenesis by inducing oxidative stress. IMiDs are bioactivated by horseradish peroxidase to generate reactive oxygen species (ROS), which cause oxidative damage to DNA. The induction of oxidative stress in the developing limb buds suppresses NF-κB activity, culminating in the downregulation of FGF and the induction of apoptosis, contributing to teratogenesis (Parman et al., 1999). Lastly, IMiDs can intercalate DNA at GC-rich sequences, stimulating epigenetic silencing of GC-rich promoters by DNA methylation and histone acetylation. This inhibits the expression of FGF-2,  affecting angiogenesis and embryonic limb development (Shortt et al., 2013). Therefore, the anti-angiogenic, pro-apoptotic, oxidative and epigenetic effects combine to induce teratogenicity.

Finally, thalidomide and its analogues are also potent inhibitors of the inflammatory response, making them effective treatments against inflammatory conditions such as leprosy and tuberculosis (TB). Leprosy and TB patients exhibit elevated cellular levels of TNF-α, a pro-inflammatory signalling protein, and IMiDs accelerate the degradation of  TNF-α mRNA (Moreira et al., 1993).